Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Published

Journal Article

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Full Text

Duke Authors

Cited Authors

  • Zekavat, SM; Ruotsalainen, S; Handsaker, RE; Alver, M; Bloom, J; Poterba, T; Seed, C; Ernst, J; Chaffin, M; Engreitz, J; Peloso, GM; Manichaikul, A; Yang, C; Ryan, KA; Fu, M; Johnson, WC; Tsai, M; Budoff, M; Vasan, RS; Cupples, LA; Rotter, JI; Rich, SS; Post, W; Mitchell, BD; Correa, A; Metspalu, A; Wilson, JG; Salomaa, V; Kellis, M; Daly, MJ; Neale, BM; McCarroll, S; Surakka, I; Esko, T; Ganna, A; Ripatti, S; Kathiresan, S; Natarajan, P; NHLBI TOPMed Lipids Working Group,

Published Date

  • July 4, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 2606 -

PubMed ID

  • 29973585

Pubmed Central ID

  • 29973585

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-04668-w

Language

  • eng